The American Society for Microbiology (ASM) is responding to the National Institutes of Health’s (NIH) Office of Biotechnology Activities (OBA) request for public comments on its February 21, 2013 Federal Register announcement regarding changes to the NIH Recombinant DNA Molecules guidelines. These guideline changes involve enhanced biosafety and occupational health practices for facilities engaged in research on mammalian-transmissible highly pathogenic avian influenza (HPAI) H5N1 viruses. The measures result from a January 2013 public meeting held by the NIH Recombinant DNA Advisory Committee (the RAC) with participation by a number of stakeholders, federal agencies and the World Health Organization. The amendments to the NIH guidelines are considered to be “minor actions” that are immediately implemented upon their publication in the Federal Register, as occurred with the February 21 announcement. The NIH and the RAC are to be commended for using a more extensive deliberative process to arrive at these enhancements and for seeking further public comments should future revisions to the guidelines be needed, even though neither step is required for implementation of a minor action.

As mentioned in the Federal Register announcement, research experiments designed to generate laboratory derived mammalian-transmissible HPAI H5N1 viruses have been highly controversial because of the potential pandemic threat posed by these agents. This controversy led to a year-long moratorium on the conduct of this type of research during which the benefits and risks of “gain-of-function” H5N1 experiments were examined in great detail. The ASM contributed to these discussions through participation in meetings and publications in its journals. Given this history, the high visibility of these experiments, and the impact the changes have on where H5N1 gain-of-function research can be performed, the ASM believes the modifications to the NIH RAC guidelines represent more than “minor actions” and the NIH would have benefitted from more extensive input from those who believe the requirements should be more or less stringent before they were implemented.

The ASM shares the consensus of the H5N1 gain-of-function meeting held at the NIH last year regarding the importance of conducting this category of research in order to inform the development of prevention and control measures for H5N1 lineage viruses and other influenza viruses with pandemic potential. The ASM recognizes that this is not a unanimous view and that there are those who view the risks of conducting and disseminating H5N1 gain-of-function research outweigh the benefits. The ASM appreciates the challenge of balancing the scientific benefits in conducting this research with the need to assure safeguards are in place to minimize the risk of inadvertent escape of these viruses from the laboratory environment. Such an escape could have devastating public health consequences.

To assure comprehensive safeguards are in place, the federal government has developed and finalized a number of policies and procedures. These include:

A framework for review and approval of gain-of-function research on HPAI H5N1 viruses that goes above and beyond the standard review process for federally funded life sciences research.

A policy related to “dual use research of concern” (DURC) involving a specific set of pathogens that includes HPAI viruses like H5N1

Proposed guidance for institutional oversight of DURC that covers H5N1 experimentation (whether or not the research involves gain-of-function)

The Centers for Disease Control and Prevention (CDC) continues to seek public comment on whether HPAI H5N1 should be added to the human select agent list (HPAI viruses are already US Department of Agriculture select agents)

The ASM strongly supports the recently adopted US government oversight system for evaluating gain-of-function research to assure that the research has scientific merit, the benefits outweigh the risks, and the necessary safeguards are in place. The ASM believes that each gain-of-function experiment involving H5N1 should be evaluated for scientific and public health benefit, to assess risks, and to identify ways to mitigate the risks (including the necessary level of bio-containment). The ASM believes such oversight should be applied globally to assure equal levels of protection are present in settings outside of the United States and at laboratories within the United States not receiving federal funding which are not mandated to adhere to the NIH RDNA Guidelines.

The February 21 changes to the NIH guidelines add another layer of requirements for research on the subset of experiments that are designed to produce, or may result in, mammalian-transmissible HPAI H5N1 viruses. ASM understands and agrees with the need to enhance the oversight and safeguards for H5N1 experimentation, recognizing that the cumulative impacts of these requirements may dissuade many investigators in the United States from working on these viruses.

The ASM supports many of the changes in the February 21st guidelines and believes they are appropriate for current circumstances where human H5N1 illness remains sporadic and there is no evidence of sustained person-to-person transmission of this viral lineage. In the event of sustained, naturally-occurring person-to-person transmission of H5N1, the ASM believes that the NIH recombinant guidelines will be too restrictive and will hinder the development of new vaccines and therapeutics that would be critical for controlling such a natural outbreak. The guidelines should specifically indicate that the additional restrictions would not apply to research conducted in the setting of a global public health emergency. If such a situation were to arise, the NIH should clearly communicate to the research community which requirements are lifted and for which categories of experiments.

There are some concerns that should be taken into consideration. These concerns are in the physical and biosafety requirements as well as the occupational health component.

The physical and biosafety procedures contain requirements that are not normally part of biosafety level (BSL) 3+ standards. As such, the requirements for work on this subset of experiments fall into a category that is somewhere in between BSL 3+ and BSL 4 (e.g. BSL3+ “enhanced”). These requirements include (1) the need for HEPA filtration of all of the laboratory’s exhaust air (2) the shower-out requirements and (3) utilization of the two-person (or “buddy”) rule when conducting such experiments. These requirements will exclude many research institutions from engaging in this type of research unless they are able to undertake extensive modifications, retrofitting, and/or enlargement of their laboratories. Such renovations in the physical plant are likely to be costly. The ASM views any requirements that greatly restrict where H5N1 gain-of-function research can be performed as appropriate only if they accomplish the intended safeguards and that equivalent protection cannot be achieved by other means.

ASM believes that institutions wishing to conduct such research and the agencies supporting research on mammalian-transmissible H5N1 must provide sufficient funds to cover any needed laboratory renovations or additional procedures that are required to meet the NIH RAC guideline standards. Such infrastructure investments are critical to ensure that appropriate containment is in place and reassure the public of the safety of such research.

The ASM recommends that each of the enhanced requirements be closely examined to (1) determine their added benefit and (2) whether alternatives can offer an equivalent degree of protection. As an example, video surveillance of the laboratory may suffice rather than the physical presence of two persons, and may be preferable in smaller laboratories where crowding could enhance risk.

The occupational health requirements should also be examined to determine whether alternatives may be available that offer equivalent safeguards to those currently in the guidelines. This is relevant in this situation since there are preventive and therapeutic measures, including antiviral agents and vaccines, available for influenza viruses. ASM recognizes that antivirals and vaccines offer variable protection against seasonal strains of influenza and would not substitute for the containment measures found in the RAC guidelines. These measures have been even less well assessed for H5N1 viruses. Nevertheless, they do offer potential options that are generally not available for other high containment pathogens.

The current guidelines prohibit home supplies of antiviral agents out of concern that an exposed individual may self-medicate and not report a respiratory illness. Such a prohibition represents an intrusion into the personal health and privacy not only of the laboratory researcher but also members of their household. Such a prohibition is likely to be unenforceable by the institution or the federal government and sets an unfortunate precedent, especially for individuals who have already signed a pledge to act responsibly. The ASM supports the need to educate any researcher engaged in H5N1 gain-of-function research about the need to promptly report any respiratory illness that occurs while engaged in these experiments, to seek immediate evaluation and treatment in a facility that can provide adequate containment to reduce the risk of transmission, and to assure appropriate follow-up of potentially exposed contacts.

ASM recognizes that for many circumstances quarantine in a medical facility or other non-community setting may be required in situations where a worker has “had a potential high risk exposure to the virus” but is not ill. However, there may be some circumstances where alternative quarantine settings could be considered, especially if antiviral prophylaxis is known to be effective and promptly initiated and the virus being used in the laboratory is known to be susceptible. In addition, the duration of quarantine should be specified.

ASM has concerns that the statement in the NIH RAC guidelines that the enhanced BSL3+ practices should be considered for “…experiments involving any influenza virus for which there is little or no community immunity (high pandemic risk) if the experiment is designed to increase transmissibility in mammals by respiratory droplets….” may be overly broad. There are many unique features to HPAI H5N1 (especially its lethality) that make it worthy of special precautions. Other influenza viruses with similar characteristics may also emerge in the future where similar enhanced measures may be appropriate for these types of experiments. However, the 2009 pandemic H1N1 virus also fit this criterion and overall severity of illness was lower for this virus than with seasonal influenza strains. Such a broad requirement may dissuade many institutions in the United States from engaging in research involving novel influenza viruses, even if these institutions are not performing gain-of-function research. ASM recommends that the guidelines be modified to indicate that each circumstance be individualized rather than making broad statements about influenza viruses with pandemic potential. If there are other viruses with similar characteristics to HPAI H5N1 and gain-of-function research will be carried out, the NIH should issue specific guidance regarding the appropriate level of containment and other safeguards that should be used

ASM appreciates the opportunity to provide feedback on the guidelines and the difficult and unique challenges associated with gain-of-function H5N1 related research. ASM looks forward to continued dialogue with NIH, the RAC, and the federal government on the various initiatives to maximize the benefit and assure the safety of high consequence life sciences research.